Publications by authors named "Ravins Dohare"

30 Publications

  • Page 1 of 1

Comprehensive Integrative Analysis Reveals the Association of with Macrophage Infiltration and Polarization in Lung Cancer Microenvironment.

Cells 2021 Aug 14;10(8). Epub 2021 Aug 14.

Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India.

Macrophage polarization and infiltration to the tumor microenvironment (TME) is a critical determining factor for tumor progression. Macrophages are polarized into two states-M1 (pro-inflammatory, anti-tumorigenic and stimulated by LPS or ) and M2 (anti-inflammatory pro-tumorigenic and stimulated by ) phenotypes. Specifically, M2 macrophages enhance tumor cell growth and survival. Recent evidences suggest the pivotal role of microRNAs in macrophage polarization during the development of Non-small cell lung cancer (NSCLC), thus proposing a new therapeutic option to target lung cancer. In silico analysis determined cogent upregulation of , downregulation of and miR-34a-5p in NSCLC tissues, consequently worsening the overall survival of NSCLC patients. We observed a significant association of with macrophage infiltration and polarization in NSCLC. We found that is critically implicated in M2 polarization of macrophages, which, in turn, promotes tumorigenesis. expression correlated with miR-34a-5p and in a feed-forward loop (FFL), both of which are implicated in immune regulation. Mechanistic overexpression of miR-34a-5p in macrophages ( stimulated) inhibits , along with downregulation of , (M2 macrophage specific markers), and upregulation of , , (M1 macrophage specific markers), demonstrating macrophage polarization switch from M2 to M1 phenotype. Moreover, co-culture of these macrophages with NSCLC cells reduces their proliferation, wound healing, clonogenic capacity and enhanced NO-mediated apoptosis. Further, transfection of miR-34a-5p in NSCLC cells, also degrades , but enhances the expression of regulated genes-, (pro-inflammatory mediators), which is further enhanced upon co-culture with stimulated macrophages. Additionally, we observed a significant increase in /NO content upon co-culture, suggesting polarization reversion of macrophages from M2 to M1, and eventually leading to anti-tumor effects. Our findings thus show a significant role of in tumorigenesis and TAM polarization of NSCLC. However, miR-34a-5p mediated targeting of these molecular networks will provide a better therapeutic intervention for NSCLC.
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http://dx.doi.org/10.3390/cells10082091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392240PMC
August 2021

Survival-Based Biomarker Module Identification Associated with Oral Squamous Cell Carcinoma (OSCC).

Biology (Basel) 2021 Aug 8;10(8). Epub 2021 Aug 8.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.

Head and neck squamous cell carcinoma (HNSC) is one of the most common malignant tumors worldwide with a high rate of morbidity and mortality, with 90% of predilections occurring for oral squamous cell carcinoma (OSCC). Cancers of the mouth account for 40% of head and neck cancers, including squamous cell carcinomas of the tongue, floor of the mouth, buccal mucosa, lips, hard and soft palate, and gingival. OSCC is the most devastating and commonly occurring oral malignancy, with a mortality rate of 500,000 deaths per year. This has imposed a strong necessity to discover driver genes responsible for its progression and malignancy. In the present study we filtered oral squamous cell carcinoma tissue samples from TCGA-HNSC cohort, which we followed by constructing a weighted PPI network based on the survival of patients and the expression profiles of samples collected from them. We found a total of 46 modules, with 18 modules having more than five edges. The KM and ME analyses revealed a single module (with 12 genes) as significant in the training and test datasets. The genes from this significant module were subjected to pathway enrichment analysis for identification of significant pathways and involved genes. Finally, the overlapping genes between gene sets ranked on the basis of weighted PPI module centralities (i.e., degree and eigenvector), significant pathway genes, and DEGs from a microarray OSCC dataset were considered as OSCC-specific hub genes. These hub genes were clinically validated using the IHC images available from the Human Protein Atlas (HPA) database.
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http://dx.doi.org/10.3390/biology10080760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389591PMC
August 2021

Revealing new therapeutic opportunities in hypertension through network-driven integrative genetic analysis and drug target prediction approach.

Gene 2021 Oct 19;801:145856. Epub 2021 Jul 19.

Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India. Electronic address:

Epidemiological studies have established that untreated hypertension (HTN) is a major independent risk factor for developing cardiovascular diseases (CVD), stroke, renal failure, and other conditions. Several important studies have been published to prevent and manage HTN; however, antihypertensive agents' optimal choice remains controversial. Therefore, the present study is undertaken to update our knowledge in the primary treatment of HTN, specifically in the setting of other three important diseases. MicroRNAs (miRNAs) are remarkably stable short endogenous conserved non-coding RNAs that bind to the mRNA at its (3' UTR) to regulate its gene expression by causing translational repression or mRNA degradation. Through their coordinated activities on different pathways and networks, individual miRNAs control normal and pathological cellular processes. Therefore, to identify the critical miRNA-mRNA-TF interactions, we performed systematic bioinformatics analysis. We have also employed the molecular modelling and docking approach to identify the therapeutic target that delivers novel empathies into Food and Drug Administration approved and herbal drug response physiology. Gene Expression Omnibus (GEO) was employed to identify the differentially expressed genes (DEGs) and hub genes- KNG1, HLA-DPB1, CXCL8, IL1B, and BCL2. The HTN associated feed-forward loop (FFL) network included miR-9-5p, KNG1 and AR. We employed high throughput screening to get the best interacting compounds, telmisartan and limonin, that provided a significant docking score (-13.3 and -12.0 kcal/mol) and a potential protective effect that may help to combat the impact of HTN. The present study provides novel insight into HTN etiology through the identification of mRNAs and miRNAs and associated pathways.
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http://dx.doi.org/10.1016/j.gene.2021.145856DOI Listing
October 2021

Identification of robust genes in transcriptional regulatory network of Mycobacterium tuberculosis.

IET Syst Biol 2020 10;14(5):292-296

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.

About 30% of the world population is infected with Mycobacterium tuberculosis (MTB). It is well known that the gene expression in MTB is highly variable, thus screening of traditional single-gene in MTB has been incapable to meet the desires of clinical diagnosis. In this report, the authors systemically analysed the transcription regulatory network (TRN) in MTB The complex interplay of these gene interactions has been revealed using exhaustive topological and global analysis of TRN using parameters including indegree, outdegree, degree, directed and undirected average path length (APL), and randomly performed. Results from indegree analysis reveal a set of important genes, including and which are associated with high indegree values. Gene ontology analysis suggested their importance in the virulence of MTB. In addition, APL and analysis of highly significant genes further identified some critical genes with different APL values. Among the list of genes identified, the gene has the shortest directed APL score and high outdegree value, thus suggesting their importance in maintaining network topology. This study provides a comprehensive analysis of TRN and offers a good basis of understanding for developing experimental study in search of new therapeutic targets against MTB H37Rv pathogen.
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http://dx.doi.org/10.1049/iet-syb.2020.0039DOI Listing
October 2020

Inhibition of miRNA-34a Promotes M2 Macrophage Polarization and Improves LPS-Induced Lung Injury by Targeting Klf4.

Genes (Basel) 2020 08 20;11(9). Epub 2020 Aug 20.

Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India.

Acute respiratory distress syndrome (ARDS) is an outcome of an accelerated immune response that starts initially as a defensive measure, however, due to non-canonical signaling, it later proves to be fatal not only to the affected tissue but to the whole organ system. microRNAs are known for playing a decisive role in regulating the expression of genes involved in diverse functions such as lung development, repair, and inflammation. In-silico analyses of clinical data and microRNA databases predicted a probable interaction between miRNA-34a (miR-34a), mitogen-activated protein kinase 1 (ERK), and kruppel like factor 4 (Klf4). Parallel to in silico results, here, we show that intra-tracheal instillation of lipopolysaccharides (LPS) to mice enhanced miR-34a expression in lung macrophages. Inhibition of miR-34a significantly improved lung histology, whereas over-expression of miR-34a worsened the lung injury phenotype. miR-34a over-expression in macrophages were also demonstrated to favour pro-inflammatory M1 phenotype and inhibition of M2 polarization. In a quest to confirm this likely interaction, expression profiles of Klf4 as the putative target were analyzed in different macrophage polarizing conditions. Klf4 expression was found to be prominent in the miR-34a inhibitor-treated group but down-regulated in the miR-34a mimic treated group. Immuno-histopathological analyses of lung tissue from the mice treated with miR-34a inhibitor also showed reduced inflammatory M1 markers as well as enhanced cell proliferation. The present study indicates that miR-34a intensified LPS-induced lung injury and inflammation by regulating Klf4 and macrophage polarization, which may serve as a potential therapeutic target for acute lung injury/ARDS.
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http://dx.doi.org/10.3390/genes11090966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563942PMC
August 2020

Unravelling host-pathogen interactions: ceRNA network in SARS-CoV-2 infection (COVID-19).

Gene 2020 Dec 15;762:145057. Epub 2020 Aug 15.

Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India. Electronic address:

COVID-19 is a lurking calamitous disease caused by an unusual virus, SARS-CoV-2, causing massive deaths worldwide. Nonetheless, explicit therapeutic drugs or clinically approved vaccines are not available for COVID-19. Thus, a comprehensive research is crucially needed to decode the pathogenic tools, plausible drug targets, committed to the development of efficient therapy. Host-pathogen interactions via host cellular components is an emerging field of research in this respect. miRNAs have been established as vital players in host-virus interactions. Moreover, viruses have the capability to manoeuvre the host miRNA networks according to their own obligations. Besides protein coding mRNAs, noncoding RNAs might also be targeted in infected cells and viruses can exploit the host miRNA network via ceRNA effect. We have predicted a ceRNA network involving one miRNA (miR-124-3p), one mRNA (Ddx58), one lncRNA (Gm26917) and two circRNAs (Ppp1r10, C330019G07RiK) in SARS-CoV infected cells. We have identified 4 DEGs-Isg15, Ddx58, Oasl1, Usp18 by analyzing a mRNA GEO dataset. There is no notable induction of IFNs and IFN-induced ACE2, significant receptor responsible for S-protein binding mediated viral entry. Pathway enrichment and GO analysis conceded the enrichment of pathways associated with interferon signalling and antiviral-mechanism by IFN-stimulated genes. Further, we have identified 3 noncoding RNAs, playing as potential ceRNAs to the genes associated with immune mechanisms. This integrative analysis has identified noncoding RNAs and their plausible targets, which could effectively enhance the understanding of molecular mechanisms associated with viral infection. However, validation of these targets is further corroborated to determine their therapeutic efficacy.
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http://dx.doi.org/10.1016/j.gene.2020.145057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428439PMC
December 2020

Deciphering key genes and miRNAs associated with Hepatocellular carcinoma via network-based approach.

IEEE/ACM Trans Comput Biol Bioinform 2020 Aug 14;PP. Epub 2020 Aug 14.

Hepatocellular carcinoma (HCC) is a common type of liver cancer and has a high mortality world-widely. The diagnosis, prognoses, and therapeutics are very poor due to the unclear molecular mechanism of progression of the disease. To unveil the molecular mechanism of progression of HCC, we extract a large sample of mRNA expression levels from the GEO database where a total of 167 samples were used for study, and out of them, 115 samples were from HCC tumor tissue. This study aims to investigate the module of differentially expressed genes (DEGs) which are co-expressed only in HCC sample data but not in normal tissue samples. Thereafter, we identified the highly significant module of significant co-expressed genes and formed a PPI network for these genes. There were only six genes (namely, MSH3, DMC1, ALPP, IL10, ZNF223, and HSD17B7) obtained after analysis of the PPI network. Out of six only MSH3, DMC1, HSD17B7, and IL10 were found enriched in GO Term & Pathway enrichment analysis and these candidate genes were mainly involved in cellular process, metabolic and catalytic activity, which promote the development & progression of HCC. Lastly, the composite 3-node FFL reveals the driver miRNAs and TFs associated with our key genes.
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http://dx.doi.org/10.1109/TCBB.2020.3016781DOI Listing
August 2020

A Systems View of the Genome Guardians: Mapping the Signaling Circuitry Underlying Oligonucleotide/Oligosaccharide-Binding Fold Proteins.

OMICS 2020 09 11;24(9):518-530. Epub 2020 Aug 11.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.

The oligonucleotide/oligosaccharide-binding (OB)-fold domain proteins are considered as genome guardians, whose functions are extending beyond genomic stability. The broad functional diversity of the OB-fold proteins is attributed to their protein-DNA, protein-RNA, and protein-protein interactions (PPI). To understand the connectivity of the human OB-fold proteins, we report here a systems-level approach. Specifically, we mapped all human OB-fold PPI networks and evaluated topological features such as network robustness and network hub, among others. We found that the OB-fold network comprised of 227 nodes forming 5523 interactions, and has a scale-free topology having UBA52, ATR, and TP53 as leading hub proteins that control efficient communication within the network. Furthermore, four different clusters and subclusters have been identified, which are implicated in diverse cellular processes, including DNA replication, repair, maintenance of genomic stability, RNA processing, spermatogenesis, complement system, and telomere maintenance. The importance of these clusters is further strengthened by knockout studies, which showed a significant decrease in topological properties. In summary, this study provides new insights on the role of OB-fold protein as genome guardians in regard to the underlying mechanism of signaling pathways, the roles of key regulators, and thus, offers new prospects as potential targets for diagnostics and therapeutics purposes.
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http://dx.doi.org/10.1089/omi.2020.0072DOI Listing
September 2020

Transcriptomic analysis delineates potential signature genes and miRNAs associated with the pathogenesis of asthma.

Sci Rep 2020 08 7;10(1):13354. Epub 2020 Aug 7.

Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi, 110025, India.

Asthma is a multifarious disease affecting several million people around the world. It has a heterogeneous risk architecture inclusive of both genetic and environmental factors. This heterogeneity can be utilised to identify differentially expressed biomarkers of the disease, which may ultimately aid in the development of more localized and molecularly targeted therapies. In this respect, our study complies with meta-analysis of microarray datasets containing mRNA expression profiles of both asthmatic and control patients, to identify the critical Differentially Expressed Genes (DEGs) involved in the pathogenesis of asthma. We found a total of 30 DEGs out of which 13 were involved in the pathway and functional enrichment analysis. Moreover, 5 DEGs were identified as the hub genes by network centrality-based analysis. Most hub genes were involved in protease/antiprotease pathways. Also, 26 miRNAs and 20 TFs having an association with these hub genes were found to be intricated in a 3-node miRNA Feed-Forward Loop. Out of these, miR-34b and miR-449c were identified as the key miRNAs regulating the expression of SERPINB2 gene and SMAD4 transcription factor. Thus, our study is suggestive of certain miRNAs and unexplored pathways which may pave a way to unravel critical therapeutic targets in asthma.
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http://dx.doi.org/10.1038/s41598-020-70368-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414199PMC
August 2020

Unravelling the Role of miR-20b-5p, CCNB1, HMGA2 and E2F7 in Development and Progression of Non-Small Cell Lung Cancer (NSCLC).

Biology (Basel) 2020 Aug 1;9(8). Epub 2020 Aug 1.

Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India.

Lung cancer is a prime cause of worldwide cancer deaths, with non-small cell lung cancer (NSCLC) as a frequent subtype. Surgical resection, chemotherapy are the currently used treatment methods. Delayed detection, poor prognosis, tumor heterogeneity, and chemoresistance make them relatively ineffective. Genomic medicine is a budding aspect of cancer therapeutics, where miRNAs are impressively involved. miRNAs are short ncRNAs that bind to 3'UTR of target mRNA, causing its degradation or translational repression to regulate gene expression. This study aims to identify important miRNA-mRNA-TF interactions in NSCLC using bioinformatics analysis. GEO datasets containing mRNA expression data of NSCLC were used to determine differentially expressed genes (DEGs), and identification of hub genes-BIRC5, CCNB1, KIF11, KIF20A, and KIF4A (all functionally enriched in cell cycle). The FFL network involved, comprised of miR-20b-5p, CCNB1, HMGA2, and E2F7. KM survival analysis determines that these components may be effective prognostic biomarkers and would be a new contemplation in NSCLC therapeutics as they target cell cycle and immunosurveillance mechanisms via HMGA2 and E2F7. They provide survival advantage and evasion of host immune response (via downregulation of cytokines-IL6, IL1R1 and upregulation of chemokines-CXCL13, CXCL14) to NSCLC. The study has provided innovative targets, but further validation is needed to confirm the proposed mechanism.
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http://dx.doi.org/10.3390/biology9080201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465122PMC
August 2020

Structure, function and therapeutic implications of OB-fold proteins: A lesson from past to present.

Brief Funct Genomics 2020 12;19(5-6):377-389

Oligonucleotide/oligosaccharide-binding (OB)-fold proteins play essential roles in the regulation of genome and its correct transformation to the subsequent generation. To maintain the genomic stability, OB-fold proteins are implicated in various cellular processes including DNA replication, DNA repair, cell cycle regulation and maintenance of telomere. The diverse functional spectrums of OB-fold proteins are mainly due to their involvement in protein-DNA and protein-protein complexes. Mutations and consequential structural alteration in the OB-fold proteins often lead to severe diseases. Here, we have investigated the structure, function and mode of action of OB-fold proteins (RPA, BRCA2, DNA ligases and SSBs1/2) in cellular pathways and their relationship with diseases and their possible use in therapeutic intervention. Due to the crucial role of OB-fold proteins in regulating the key physiological process, a detailed structural understanding in the context of underlying mechanism of action and cellular complexity offers a new avenue to target OB-proteins for therapeutic intervention.
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http://dx.doi.org/10.1093/bfgp/elaa008DOI Listing
December 2020

Network-based identification of signature genes KLF6 and SPOCK1 associated with oral submucous fibrosis.

Mol Clin Oncol 2020 Apr 30;12(4):299-310. Epub 2020 Jan 30.

Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India.

The molecular mechanism of oral submucous fibrosis (OSF) is yet to be fully elucidated. The identification of reliable signature genes to screen patients with a high risk of OSF and to provide oral cancer surveillance is therefore required. The present study produced a filtering criterion based on network characteristics and principal component analysis, and identified the genes that were involved in OSF prognosis. Two gene expression datasets were analyzed using meta-analysis, the results of which revealed 1,176 biologically significant genes. A co-expression network was subsequently constructed and weighted gene modules were detected. The pathway and functional enrichment analyses of the present study allowed for the identification of modules 1 and 2, and their respective genes, SPARC (osteonectin), cwcv and kazal like domain proteoglycan 1 (SPOCK1) and kruppel like factor 6 (KLF6), which were involved in the occurrence of OSF. The results revealed that both genes had a prominent role in epithelial to mesenchymal transition during OSF progression. The genes identified in the present study require further exploration and validation within clinical settings to determine their roles in OSF.
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http://dx.doi.org/10.3892/mco.2020.1991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058035PMC
April 2020

Structural Features of Nucleoprotein CST/Shelterin Complex Involved in the Telomere Maintenance and Its Association with Disease Mutations.

Cells 2020 02 4;9(2). Epub 2020 Feb 4.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.

Telomere comprises the ends of eukaryotic linear chromosomes and is composed of G-rich (TTAGGG) tandem repeats which play an important role in maintaining genome stability, premature aging and onsets of many diseases. Majority of the telomere are replicated by conventional DNA replication, and only the last bit of the lagging strand is synthesized by telomerase (a reverse transcriptase). In addition to replication, telomere maintenance is principally carried out by two key complexes known as shelterin (TRF1, TRF2, TIN2, RAP1, POT1, and TPP1) and CST (CDC13/CTC1, STN1, and TEN1). Shelterin protects the telomere from DNA damage response (DDR) and regulates telomere length by telomerase; while, CST govern the extension of telomere by telomerase and C strand fill-in synthesis. We have investigated both structural and biochemical features of shelterin and CST complexes to get a clear understanding of their importance in the telomere maintenance. Further, we have analyzed ~115 clinically important mutations in both of the complexes. Association of such mutations with specific cellular fault unveils the importance of shelterin and CST complexes in the maintenance of genome stability. A possibility of targeting shelterin and CST by small molecule inhibitors is further investigated towards the therapeutic management of associated diseases. Overall, this review provides a possible direction to understand the mechanisms of telomere borne diseases, and their therapeutic intervention.
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http://dx.doi.org/10.3390/cells9020359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072152PMC
February 2020

Investigation of conformational dynamics of Tyr89Cys mutation in protection of telomeres 1 gene associated with familial melanoma.

J Biomol Struct Dyn 2021 Jan 27;39(1):35-44. Epub 2019 Dec 27.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.

Protection of telomeres 1 (POT1) is a component of the shelterin complex which is crucial for the regulation of telomere length and maintenance. Many naturally occurring mutations in the POT1 gene have been found to be associated with cardiac angiosarcoma, glioma, familial melanoma, and chronic lymphocytic leukemia. In particular, Y89C is a naturally occurring mutation of POT1, responsible for familial melanoma, and the molecular basis of this mutation is unexplored. In this study, we have extensively analyzed the structure of WT and Y89C mutant of POT1 to see the change in the conformational dynamics, free energy landscape, molecular motions and configurational frustration using molecular dynamics (MD) and other bioinformatics approaches. Y89C mutation shows a significant change in the backbone orientation, compactness, residual fluctuation, solvent accessibility, and hydrogen bonding, suggesting an overall destabilization of the protein structure. Besides, essential dynamics, conformation, magnitude, direction of motion and frustration analysis further suggesting the structural loss in POT1 due to Y89C mutation. Free energy landscape analysis also indicates the presence of a single well-defined free-energy minima in case of WT compared to multiple wells defined free energy minima observed in Y89C, clearly suggesting that this mutation leads to reduce the stability of POT1. This study possibly provides a valuable path to understand the molecular basis of Y89C-mediated development of familial melanoma.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2019.1705186DOI Listing
January 2021

Transcriptome Meta-Analysis Deciphers a Dysregulation in Immune Response-Associated Gene Signatures during Sepsis.

Genes (Basel) 2019 12 4;10(12). Epub 2019 Dec 4.

Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India.

Sepsis is a life-threatening disease induced by a systemic inflammatory response, which leads to organ dysfunction and mortality. In sepsis, the host immune response is depressed and unable to cope with infection; no drug is currently available to treat this. The lungs are frequently the starting point for sepsis. This study aimed to identify potential genes for diagnostics and therapeutic purposes in sepsis by a comprehensive bioinformatics analysis. Our criteria are to unravel sepsis-associated signature genes from gene expression datasets. Differentially expressed genes (DEGs) were identified from samples of sepsis patients using a meta-analysis and then further subjected to functional enrichment and protein‒protein interaction (PPI) network analysis for examining their potential functions. Finally, the expression of the topmost upregulated genes (, , , ) was quantified by reverse transcriptase-PCR (RT-PCR), and myeloperoxidase () expression was confirmed by immunohistochemistry (IHC) staining in the lungs of a well-established sepsis mouse model. We found that all the four genes were upregulated in semiquantitative RT-PCR studies; however, showed a nonsignificant increase in expression. staining showed strong immunoreactivity in sepsis as compared to the control. This study demonstrates the role of significant and widespread immune activation (, ), along with oxidative stress () and the recruitment of neutrophils, in sepsis (, ).
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http://dx.doi.org/10.3390/genes10121005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947644PMC
December 2019

Virtual high-throughput screening of natural compounds in-search of potential inhibitors for protection of telomeres 1 (POT1).

J Biomol Struct Dyn 2020 Sep 31;38(15):4625-4634. Epub 2019 Oct 31.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.

Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2019.1682052DOI Listing
September 2020

Identification of differentially expressed genes in small and non-small cell lung cancer based on meta-analysis of mRNA.

Heliyon 2019 Jun 14;5(6):e01707. Epub 2019 Jun 14.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India.

Lung cancer has the lowest survival rate spread globally resulting in a large number of deaths. This is attributed to insufficient measures such as lack of early detection and chemoresistance in the patients. It can be subdivided into two histological groups: Non-Small-Cell Lung Cancer (NSCLC), which is most prevalent (85% of all lung cancers) but less destructive; and Small-Cell Lung Cancer (SCLC), which is intermittently metastatic and less prevalent (15% of all lung cancers). The present study deals with the analysis of gene expression of two subtypes to identify the Differentially Expressed Genes (DEGs). For this study, we selected two datasets from the Omnibus database, which included 50 non-small cell lung cancer samples, 31 small cell lung cancer samples, and 48 samples from normal lung tissue. After DEGs identification using the meta-analysis approach, they were then subjected to further analysis following p-value adjustment via the Benjamini-Hochberg method. We identified 440 overexpressed and 489 underexpressed genes in NSCLC, and 489 overexpressed and 525 underexpressed genes in SCLC, compared with normal lung tissues. Furthermore, we identified 3 overlapping genes between upregulated DEGs in NSCLC and downregulated DEGs in SCLC; and 8 overlapping genes between upregulated DEGs in SCLC and downregulated DEGs in NSCLC. Accordingly, a Protein-Protein Interaction (PPI) network of the overlapping genes was generated, which contained a total of 261 genes, of which the top five were TRIM29, ANK3, CSTA, FGG, and AGR2. These five candidate genes reported herein may prove to be potential therapeutic targets.
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http://dx.doi.org/10.1016/j.heliyon.2019.e01707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580189PMC
June 2019

Impact of length of replication competent genome of hepatitis B virus over the differential antigenic secretion.

J Cell Biochem 2019 10 16;120(10):17858-17871. Epub 2019 Jul 16.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.

Hepatitis B virus (HBV) genome consists of circular partially double stranded DNA of 3.2 kb size which gets converted into covalently closed circular DNA (cccDNA) during its life cycle. It then acts as a template for formation of pregenomicRNA (pgRNA) of 3.5 kb. Absence of appropriate animal models prompted a need to establish a better in vitro culture system to uncover the propagation and survival mechanisms of the virus. There is scarcity of data to represent the significance of varying length of replication competent viral genome on the secretion of viral secretory proteins/antigens and in turn on the overall effects on the accomplishment of the viral life cycle. The present study was undertaken to ascertain a suitable replication competent construct in which the viral life cycle of HBV with varying clinical relevance can be studied efficiently. Two constructs (pHBV 1.3 and pHBV 1X) of different sizes were used to transfect hepatoma cells and consequently the secretory antigens were monitored. In vector free approach (pHBV 1X), 3.2 kb viral DNA is directly transfected in the culture system whereas in vector mediated approach more than full length of viral genome is cloned in a vector (pHBV 1.3X) and transfected to obtain a 3.5 kb pgRNA intermediate. HBV secretes two important antigens; HBsAg and HBeAg. HBsAg is a hallmark of infection and is the first to be secreted in the blood stream whereas HBeAg is a secretory protein and remains associated with the viral replication. The construct pHBV 1.3X referring to as more than full length, by virtue of being capable of undergoing transcription without the synthesis of cccDNA intermediate (unlike the clinical situation where an intermediate step of cccDNA synthesis is an essential component to initiate the viral life cycle) appears to be better system for studying viral life cycle in in vitro culture system. The reasons could be assigned to the fact that as low as 100 ng of viral DNA was shown to quantify the replicative phenotypes with this construct. The better efficiency of this construct at prima facie, appears to be mediated through the significantly higher levels of pgRNA transcript during the viral life cycle.
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http://dx.doi.org/10.1002/jcb.29054DOI Listing
October 2019

Structural Analysis and Conformational Dynamics of Gene Mutations Involved in Coat Plus Syndrome.

Front Mol Biosci 2019 12;6:41. Epub 2019 Jun 12.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.

The human CST complex (CTC1-STN1-TEN1) is associated with telomere functions including genome stability. We have systemically analyzed the sequence of STN and performed structure analysis to establish its association with the Coat Plus (CP) syndrome. Many deleterious non-synonymous SNPs have been identified and subjected for structure analysis to find their pathogenic association and aggregation propensity. A 100-ns all-atom molecular dynamics simulation of WT, R135T, and D157Y structures revealed significant conformational changes in the case of mutants. Changes in hydrogen bonds, secondary structure, and principal component analysis further support the structural basis of STN1 dysfunction in such mutations. Free energy landscape analysis revealed the presence of multiple energy minima, suggesting that R135T and D157Y mutations destabilize and alter the conformational dynamics of STN1 and thus may be associated with the CP syndrome. Our study provides a valuable direction to understand the molecular basis of CP syndrome and offer a newer therapeutics approach to address CP syndrome.
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http://dx.doi.org/10.3389/fmolb.2019.00041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581698PMC
June 2019

Structural and functional impact of non-synonymous SNPs in the CST complex subunit TEN1: structural genomics approach.

Biosci Rep 2019 05 15;39(5). Epub 2019 May 15.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India

TEN1 protein is a key component of CST complex, implicated in maintaining the telomere homeostasis, and provides stability to the eukaryotic genome. Mutations in gene have higher chances of deleterious impact; thus, interpreting the number of mutations and their consequential impact on the structure, stability, and function is essentially important. Here, we have investigated the structural and functional consequences of nsSNPs in the gene. A wide array of sequence- and structure-based computational prediction tools were employed to identify the effects of 78 nsSNPs on the structure and function of TEN1 protein and to identify the deleterious nsSNPs. These deleterious or destabilizing nsSNPs are scattered throughout the structure of TEN1. However, major mutations were observed in the α1-helix (12-16 residues) and β5-strand (88-96 residues). We further observed that mutations at the C-terminal region were having higher tendency to form aggregate. In-depth structural analysis of these mutations reveals that the pathogenicity of these mutations are driven mainly through larger structural changes because of alterations in non-covalent interactions. This work provides a blueprint to pinpoint the possible consequences of pathogenic mutations in the CST complex subunit TEN1.
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http://dx.doi.org/10.1042/BSR20190312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522806PMC
May 2019

Impact of Gln94Glu mutation on the structure and function of protection of telomere 1, a cause of cutaneous familial melanoma.

J Biomol Struct Dyn 2020 Mar 7;38(5):1514-1524. Epub 2019 May 7.

Jamia Millia Islamia, Jamia Nagar, Centre for Interdisciplinary Research in Basic Sciences, New Delhi, India.

Protection of telomere 1 (POT1) is a key component of shelterin complex, essential for maintaining telomere length and its regulation. It consists of -terminal domain (residues 1-299), which interacts with telomeric ssDNA, and the C-terminal domain (residues 320-634) that binds to the tripeptidyl-peptidase I (TPP1). A large number of naturally occurring mutations in the gene are associated with glioma, cardiac angiosarcoma and cutaneous familial melanoma (FM). In particular, Q94E mutation disrupts the interaction of POT1 with telomeric DNA which subsequently enhances telomere uncapping and elongation and promotes the development of cutaneous familial melanoma. To understand the underlying mechanism of familial melanoma developed by Q94E-mutation, we have performed extensive structure analysis of WT and mutant protein followed by molecular dynamics simulations. Q94E mutation causes a dramatic change in the structure and stability of POT1 protein. A considerable decrease in the flexibility, fluctuation and solvent accessibility of Q94E was observed in comparison to the WT, indicating overall destabilization of protein. Essential dynamics and Anisotropic Network Mode analysis have quantified a significant change in direction and magnitude of conformational motion in Q94E mutant compared to WT. A significant loss of frustration due to Q94E mutation was also observed. Our findings indicate the loss of protein stability and dynamics of POT1 protein by Q94E mutation may be associated with the familial melanoma. AbbreviationsANManisotropic network modeEDessential dynamicsFMfamilial melanomaMDmolecular dynamicsPOT1protection of telomere 1Rgradius of gyrationRMSDroot-mean-square deviationRMSFroot-mean-square fluctuationsSASAsolvent accessible surface areaSIFTsorting Intolerant from TolerantTPP1tripeptidyl-peptidase IWTwild typeCommunicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2019.1610500DOI Listing
March 2020

Investigating architecture and structure-function relationships in cold shock DNA-binding domain family using structural genomics-based approach.

Int J Biol Macromol 2019 Jul 18;133:484-494. Epub 2019 Apr 18.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India. Electronic address:

Oligonucleotide/oligosaccharide-binding fold (OB-fold) plays a major role in the regulation of central dogma of life via binding though DNA and RNA. The OB-fold domains are diverse in nature and present in large number of proteins with verities of molecular functions. Here, we have investigated the distribution of sequence, structure and repeats of cold shock DNA-binding proteins (CSDB), a member of OB-fold, in all three kingdoms to establish functional relationships. The CSDB is consists of 30 domains with a major contribution of S1 (>110,601 sequences), S12 (>23,760 sequences), S17 (>14,833 sequences) and S28e (>1615 sequence) domains. These domains are largely found in bacteria (70-90%). The number of S1 domain repeats in eukaryota varies from 1 to 15 and are well-correlated with the protein size. The molecular function analysis suggests that a large number of repeats in the S1 domain are involved in diverse molecular functions in bacteria and eukaryotes. In-depth structure analysis of S1, S12, S17 and S28e domain-containing proteins of the OB-fold family provides a reasonable basis to understand the relationship of size and number of repeats with the corresponding molecular functions.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.04.135DOI Listing
July 2019

In Vitro Cytotoxicity and Interaction of Noscapine with Human Serum Albumin: Effect on Structure and Esterase Activity of HSA.

Mol Pharm 2019 03 31;16(3):952-966. Epub 2019 Jan 31.

Biophysical Chemistry Laboratory, Centre for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia (A Central University) , New Delhi 110025 , India.

Noscapine is effective to inhibit cellular proliferation and induced apoptosis in nonsmall cell, lung, breast, lymphoma, and prostate cancer. It also shows good efficiency to skin cancer cells. In the current work, we studied the mechanism of interaction between the anticancer drug noscapine (NOS) and carrier protein human serum albumin (HSA) by using a variety of spectroscopic techniques (fluorescence spectroscopy, time-resolved fluorescence, UV-visible, fluorescence resonance energy transfer (FRET), Fourier transform infrared (FTIR), and circular dichroism (CD) spectroscopy), electrochemistry (cyclic voltammetry), and computational methods (molecular docking and molecular dynamic simulation). The steady-state fluorescence results showed that fluorescence intensity of HSA decreased in the presence of NOS via a static quenching mechanism, which involves ground state complex formation between NOS and HSA. UV-visible and FRET results also supported the fluorescence result. The corresponding thermodynamic result shows that binding of NOS with HSA is exothermic in nature, involving electrostatic interactions as major binding forces. The binding results were further confirmed through a cyclic voltammetry approach. The FRET result signifies the energy transfer from Trp214 of HSA to the NOS. Molecular site marker, molecular docking, and MD simulation results indicated that the principal binding site of HSA for NOS is site I. Synchronous fluorescence spectra, FTIR, 3D fluorescence, CD spectra, and MD simulation results reveal that NOS induced the structural change in HSA. In addition, the MTT assay study on a human skin cancer cell line (A-431) was also performed for NOS, which shows that NOS induced 80% cell death of the population at a 320 μM concentration. Moreover, the esterase-like activity of HSA with NOS was also done to determine the variation in protein functionality after binding with NOS.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00864DOI Listing
March 2019

Investigation of deleterious effects of nsSNPs in the POT1 gene: a structural genomics-based approach to understand the mechanism of cancer development.

J Cell Biochem 2019 06 16;120(6):10281-10294. Epub 2018 Dec 16.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.

Protection of telomere 1 (POT1) is one of the key components of shelterin complex, implicated in maintaining the telomere homeostasis, and thus stability of the eukaryotic genome. A large number of non-synonymous single nucleotide polymorphisms (nsSNPs) in the POT1 gene have been reported to cause varieties of human diseases, including cancer. In recent years, a number of mutations in POT1 has been markedly increased, and interpreting the effect of these large numbers of mutations to understand the mechanism of associated diseases seems impossible using experimental approaches. Herein, we employ varieties of computational methods such as PROVEAN, PolyPhen-2, SIFT, PoPMuSiC, SDM2, STRUM, and MAESTRO to identify the effects of 387 nsSNPs on the structure and function of POT1 protein. We have identified about 183 nsSNPs as deleterious and termed them as "high-confidence nsSNPs." Distribution of these high-confidence nsSNPs demonstrates that the mutation in oligonucleotide binding domain 1 is highly deleterious (one in every three nsSNPs), and high-confidence nsSNPs show a strong correlation with residue conservation. The structure analysis provides a detailed insights into the structural changes occurred in consequence of conserved mutations which lead to the cancer progression. This study, for the first time, offers a newer prospective on the role of POT1 mutations on the structure, function, and their relation to associated diseases.
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http://dx.doi.org/10.1002/jcb.28312DOI Listing
June 2019

Sequence, structure and evolutionary analysis of cold shock domain proteins, a member of OB fold family.

J Evol Biol 2018 12 19;31(12):1903-1917. Epub 2018 Oct 19.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.

The cold shock domain (CSD) belongs to the oligosaccharide/oligonucleotide-binding fold superfamily which is highly conserved from prokaryotes to higher eukaryotes, and appears to function as RNA chaperones. CSD is involved in diverse cellular processes, including adaptation to low temperatures, nutrient stress, cellular growth and developmental processes. Structural Classification of Proteins (SCOP) database broadly classifies OB fold proteins into 18 different superfamilies, including nucleic acid-binding superfamily (NAB). The NAB is further divided into 17 families together with cold shock DNA-binding protein family (CSDB). The CSDB have more than 240 000 sequences in UniProt database consisting of 32 domains including CSD. Among these domains, CSD is the second largest sequence contributor (> 40 398 sequences). Herein, we have systematically analysed the relative abundance and distribution of CSD proteins based on sequences, structures, repeats and gene ontology (GO) molecular functions in all domains of life. Analysis of sequence distribution suggesting that CSDs are largely found in bacteria (83-94%) with single CSD repeat. However, repeat distribution in eukaryota varies from 1 to 5 in combination with other auxiliary domain that makes CSD proteins functionally more diverse compared to the bacterial counterparts. Further, analysis of repeats distributions on evolutionary scale suggest that existence of CSD in multiple repeats is mainly driven through speciation, gene shuffling and gene duplication events.
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http://dx.doi.org/10.1111/jeb.13382DOI Listing
December 2018

BA9 lineage of respiratory syncytial virus from across the globe and its evolutionary dynamics.

PLoS One 2018 25;13(4):e0193525. Epub 2018 Apr 25.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.

Respiratory syncytial virus (RSV) is an important pathogen of global significance. The BA9 is one of the most predominant lineages of the BA genotype of group B RSV that has acquired a 60bp duplication in its G protein gene. We describe the local and global evolutionary dynamics of the second hyper variable region in the C- terminal of the G protein gene of the BA9 lineage. A total of 418 sequences (including 31 study and 387 GenBank strains) from 29 different countries were used for phylogenetic analysis. This analysis showed that the study strains clustered with BA (BA9 and BA8) and SAB4 genotype of group B RSV. We performed time-scaled evolutionary clock analyses using Bayesian Markov chain Monte Carlo methods. We also carried out glycosylation, selection pressure, mutational, entropy and Network analyses of the BA9 lineage. The time to the most recent common ancestor (tMRCA) of the BA genotype and BA9 lineage were estimated to be the years 1995 (95% HPD; 1987-1997) and 2000 (95% HPD; 1998-2001), respectively. The nucleotide substitution rate of the BA genotype [(4.58×10-3 (95% HPD; 3.89-5.29×10-3) substitution/site/year] was slightly faster than the BA9 lineage [4.03×10-3 (95% HPD; 4.65-5.2492×10-3)]. The BA9 lineage was categorized into 3 sub lineages (I, II and III) based on the Bayesian and Network analyses. The local transmission pattern suggested that BA9 is the predominant lineage of BA viruses that has been circulating in India since 2002 though showing fluctuations in its effective population size. The BA9 lineage established its global distribution with report from 23 different countries over the past 16 years. The present study augments our understanding of RSV infection, its epidemiological dynamics warranting steps towards its overall global surveillance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193525PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919079PMC
July 2018

Global distribution of NA1 genotype of respiratory syncytial virus and its evolutionary dynamics assessed from the past 11 years.

Infect Genet Evol 2018 06 8;60:140-150. Epub 2018 Feb 8.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India. Electronic address:

Respiratory syncytial virus (RSV) is a potent pathogen having global distribution. The main purpose of this study was to gain an insight into distribution pattern of the NA1 genotype of group A RSV across the globe together with its evolutionary dynamics. We focused on the second hypervariable region of the G protein gene and used the same for Phylogenetic, Bayesian and Network analyses. Eighteen percent of the samples collected from 500 symptomatic pediatric patients with acute respiratory tract infection (ARI) were found to be positive for RSV during 2011-15 from New Delhi, India. Of these, group B RSV was predominant and clustered into two different genotypes (BA and SAB4). Similarly, group A viruses clustered into two genotypes (NA1 and ON1). The data set from the group A viruses included 543 sequences from 23 different countries including 67 strains from India. The local evolutionary dynamics suggested consistent virus population of NA1 genotype in India during 2009 to 2014. The molecular clock analysis suggested that most recent common ancestor of group A and NA1 genotype have emerged in during the years 1953 and 2000, respectively. The global evolutionary rates of group A viruses and NA1 genotype were estimated to be 3.49 × 10 (95% HPD, 2.90-4.17 × 10) and 3.56 × 10 (95% HPD, 2.91 × 10-4.18 × 10) substitution/site/year, respectively. Analysis of the NA1 genotype of group A RSV reported during 11 years i.e. from 2004 to 2014 showed its dominance in 21 different countries across the globe reflecting its evolutionary dynamics. The Network analysis showed highly intricate but an inconsistent pattern of haplotypes of NA1 genotype circulating in the world. Present study seems to be first comprehensive attempt on global distribution and evolution of NA1 genotype augmenting the optimism towards the vaccine development.
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http://dx.doi.org/10.1016/j.meegid.2018.02.010DOI Listing
June 2018

Effect of 1-methyl-3-octyleimmidazolium chloride on the stability and activity of lysozyme: a spectroscopic and molecular dynamics studies.

J Biomol Struct Dyn 2017 Jul 5;35(9):2016-2030. Epub 2016 Aug 5.

a Biophysical Chemistry Laboratory, Centre for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia (A Central University) , New Delhi 110025 , India.

Herein, the binding of 1-methyl-3-octylimidazolium chloride [OMIM][Cl] ionic liquid with hen egg white lysozyme (HEWL) has been studied using fluorescence, time resolved fluorescence, UV-visible and circular dichroism (CD) spectroscopy, in combination with computational study. The fluorescence results revealed that [OMIM][Cl] quenches the fluorophore of HEWL through static quenching mechanism. The calculated thermodynamic parameters show that [OMIM][Cl] bind with HEWL through hydrophobic interactions. In addition, the negative value of Gibbs energy change (∆G) indicates that the binding process was spontaneous. Furthermore, UV-vis and CD results indicate that [OMIM][Cl] induce the conformational change in HEWL and increase its enzymatic activity. Additionally, molecular docking results showed that [OMIM][Cl] binds at the active site of HEWL where both the fluorophore residues (Trp108 and Trp62) and the catalytic residues (Glu35 and Asp52) reside. Molecular dynamic simulation results show the reduction of intra-molecular hydrogen bond of HEWL when it binds with [OMIM][Cl].
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http://dx.doi.org/10.1080/07391102.2016.1204946DOI Listing
July 2017

Hydrogen bonding-assisted interaction between amitriptyline hydrochloride and hemoglobin: spectroscopic and molecular dynamics studies.

J Biomol Struct Dyn 2017 May 1;35(6):1367-1380. Epub 2016 Jun 1.

a Biophysical Chemistry Laboratory, Centre for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia (A Central University) , New Delhi , India.

Herein, we have explored the interaction between amitriptyline hydrochloride (AMT) and hemoglobin (Hb), using steady-state and time-resolved fluorescence spectroscopy, UV-visible spectroscopy, and circular dichroism spectroscopy, in combination with molecular docking and molecular dynamic (MD) simulation methods. The steady-state fluorescence reveals the static quenching mechanism in the interaction system, which was further confirmed by UV-visible and time-resolved fluorescence spectroscopy. The binding constant, number of binding sites, and thermodynamic parameters viz. ΔG, ΔH, ΔS are also considered; result confirms that the binding of the AMT with Hb is a spontaneous process, involving hydrogen bonding and van der Waals interactions with a single binding site, as also confirmed by molecular docking study. Synchronous fluorescence, CD data, and MD simulation results contribute toward understanding the effect of AMT on Hb to interpret the conformational change in Hb upon binding in aqueous solution.
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http://dx.doi.org/10.1080/07391102.2016.1184184DOI Listing
May 2017

Evolutionary Analysis of Dengue Serotype 2 Viruses Using Phylogenetic and Bayesian Methods from New Delhi, India.

PLoS Negl Trop Dis 2016 Mar 15;10(3):e0004511. Epub 2016 Mar 15.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.

Dengue fever is the most important arboviral disease in the tropical and sub-tropical countries of the world. Delhi, the metropolitan capital state of India, has reported many dengue outbreaks, with the last outbreak occurring in 2013. We have recently reported predominance of dengue virus serotype 2 during 2011-2014 in Delhi. In the present study, we report molecular characterization and evolutionary analysis of dengue serotype 2 viruses which were detected in 2011-2014 in Delhi. Envelope genes of 42 DENV-2 strains were sequenced in the study. All DENV-2 strains grouped within the Cosmopolitan genotype and further clustered into three lineages; Lineage I, II and III. Lineage III replaced lineage I during dengue fever outbreak of 2013. Further, a novel mutation Thr404Ile was detected in the stem region of the envelope protein of a single DENV-2 strain in 2014. Nucleotide substitution rate and time to the most recent common ancestor were determined by molecular clock analysis using Bayesian methods. A change in effective population size of Indian DENV-2 viruses was investigated through Bayesian skyline plot. The study will be a vital road map for investigation of epidemiology and evolutionary pattern of dengue viruses in India.
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http://dx.doi.org/10.1371/journal.pntd.0004511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792444PMC
March 2016
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